We previously reported that immunization with recombinant SIVmne envelope (gp160) vaccines protected macaques against an intravenous challenge by the cloned homologous virus, E11S. In this study, we confirmed this observation and found that the vaccines were effective not only against virus grown on human T-cell lines, but also against virus grown on macaque PBMC. The breadth of protection, however, was limited. In three experiments, 3/10 animals challenged with the parental uncloned SIVmne were completely protected. Of the remaining animals, three were transiently virus-positive and four were persistently positive after challenge, as were 10 non-immunized control animals. Protection was not correlated with levels of serum-neutralizing antibodies against the homologous SIVmne or a related virus, SIVmac251. To gain further insight into the protective mechanism, we analyzed nucleotide sequences in the envelope region of the uncloned challenge virus and compared them w ith those present in the PBMC of infected animals. The majority (85%) of the uncloned challenge virus was homologous to the molecular clone from which the vaccines were made (E11S type). The remaining 15% contained conserved changes in the V1 region (variant types). Control animals infected with this uncloned virus had varying proportions of both genotypes, whereas 3/4 immunized but persistently infected animals had >99% of the variant types early after infection. These results indicate that the protective immunity elicited by recombinant gp160 vaccines is restricted primarily to the homologous virus and suggest the possibility that immune responses directed to the V1 region of the envelope protein may play a role in protection. The results of this study were published in early 1999. FUNDING NIH grant RR00166. Polacino, P., V. Stallard, J. E. Klaniecki, D. C. Montefiori, A. J. Langlois, B. A. Richardson, J. Overbaugh, W. R. Morton, R. E. Benveniste, and S. L. Hu. 1999. Limited breadth of the protective immunity elicited by simian immunodeficiency virus SIVmne gp160 vaccines in a combination immunization regimen. J. Virol. 73:618-630.